WO2018170997A1 - Method for preparing compound - Google Patents

Abstract

Provided is a method for preparing a compound represented by formula I by means of a compound represented by formula (II), wherein the definitions of each group are as described in the description. Said route has the characteristics of being industrially producible, being high yield, the product thereof being easily separated, and the like; the compound represented by formula (I) is a multi-target tyrosine protein kinase inhibitor having good anti-tumor activity.

Description

Method for preparing a compound Technical field

The present invention belongs to the field of pharmaceutical synthesis, and in particular, the present invention relates to a process for synthesizing quinoline compounds.

Background technique

Protein tyrosine kinase (PTK) is a class of proteins with protein tyrosine kinase activity that catalyzes the transfer of phosphogenes on ATP to many protein tyrosine residues associated with cellular life activities, allowing them to undergo phosphoric acid Chemical. The protein tyrosine kinase signaling pathway is involved in the regulation, signaling, transmission and development of normal cells, and is also closely related to the proliferation, differentiation, migration and apoptosis of tumor cells.

The vascular endothelial growth factor receptor VEGFR is activated during many cancer developments leading to angiogenesis. Vascular endothelial growth factor-A (VEGF-A), a key member of angiogenesis, acts by binding to VEGFR-1 and VERFR-2. Vascular endothelial growth factor receptors further activate downstream signaling pathways in the network, including the phosphatidylinositol-3-kinase/protein kinase B signaling pathway. Immunohistochemistry experiments showed that VEGF and VEGFR were over-expressed in tumor patients, suggesting that vascular endothelial growth factor receptor activation plays an important role in tumor growth.

Angiogenesis plays an important role in the growth, development, reproduction, and wound healing of the organism. The growth and metastasis of the primary tumor also depends on angiogenesis. New tumors require more blood vessels to meet their metabolic and proliferation needs. The blood circulation spreads to other tissues and organs. Angiogenesis is a key factor in tumor growth, providing not only nutrition and oxygen to the tumor, but also the pathway through which tumor cells enter the system's circulation and metastasis. A variety of angiogenic factors secreted by tumor cells are interconnected and regulated. Among the many factors that regulate the formation of new blood vessels, vascular endothelial growth factor (VEGF) is one of the main factors inducing angiogenesis, and it is the most potent and most specific positive regulator. In one, it binds to the corresponding vascular endothelial growth factor receptor (VEGF receplor, VEGFR) and stimulates the proliferation and migration of endothelial cells through specific signal transduction pathways, thereby promoting the formation of new blood vessels.

VEGF, also known as vascular permeability factor, is a powerful cytokine that produces a variety of biological functions. In 1989, Ferrarra was a kind of glycoprotein isolated and purified from bovine pituitary follicular stellate cell culture medium. A member of the Platelet derived growth factor (PDGF) family, with a molecular weight of 34-45KD, is highly conserved and widely distributed in tissues such as brain, kidney, spleen, pancreas and bone in humans and animals. Factor, extracellular factor, hypoxia, regulation of P53 gene. VEGFR binds to its ligand VEGF to produce a range of physiological and biochemical processes that ultimately promote neovascularization. In normal blood vessels, angiogenic factors and angiogenesis inhibitors maintain a relatively balanced level, and during tumor growth, high expression of VEGFR and VEGF disrupts this balance and promotes tumor angiogenesis.

c-Met, also known as MET or HGFR, is a protein product encoded by the MET proto-oncogene (mainly present in stem cells, progenitor cells), a hepatocyte growth factor transmembrane receptor with tyrosine kinase activity. c-Met is mainly expressed in epithelial fine Cells, also found in endothelial cells, hepatocytes, nerve cells and hematopoietic cells, play an important role in embryonic development and wound healing. Hepatocyte growth factor (HGF) is the only ligand of c-Met receptor secreted by mesenchymal cells.

The c-Met receptor plays an important role in the cell metabolism, differentiation and signal transduction of cell apoptosis. It binds to the ligand and activates five downstream signal transduction pathways, such as RAS/RAF and phosphatidylcholine. Alcohol 3 kinase (PI3K), signal transduction and transcriptional activator (STAT), Notch and Beta-catenin promote cell mitosis, morphogenesis and other biological reactions, thereby participating in embryonic development, tissue damage repair, liver regeneration and tumor invasion. And transfer.

Hepatocyte growth factor (HGF), also known as a dispersing factor, is a ligand for the tyrosine kinase variant c-Met and acts as a derivative of fibroblasts that induce epithelial cell dispersion, contributing to many epithelial cells. Mitosis, the role of induced morphological changes. In addition, HGF stimulates vascular endothelial growth factor and upregulates the expression of molecules and their receptors involved in extracellular matrix proteolysis. In order to produce an effect (biological effect), HGF must bind to its receptor c-Met, the receptor tyrosine kinase. The specific membrane receptor for HGF is the expression product of the proto-oncogene c-Met, which is located on chromosome 7q31 and has a size of 110 kb containing 21 exons. Its promoter domain includes many regulatory sequences such as AP1, AP2, NF2JB, and SP1.

HGF specifically binds to the c-Met receptor protein, induces a conformational change in the C-Met receptor protein, and activates the tyrosine protein kinase (PTK) in the receptor's intracellular protein kinase domain, which is HGF/c- The primary link of the Met signal transduction pathway. In most tumor cells, the tyrosine residue of the 4-phosphorylation site near c-Met near the intracellular region undergoes autophosphorylation, followed by a series of phosphorylation reactions to activate phospholipase (PLCγ), phosphoinositide 3 Tyrosine phosphorylation of proteins such as kinase (PI3K), Ras protein, SγC protein, adaptor protein Gabl and growth factor receptor binding protein 2 (Gγb2). Through the waterfall-type phosphorylation reaction, the signal is amplified step by step, and finally transferred to the transcription mechanism in the nucleus, thereby regulating the proliferation, migration and invasion ability of the tumor cells.

HGF and c-Met regulate growth, angiogenesis, invasiveness and metastasis in many human cancers and promote tumors. Activation of c-Met expression is caused by hypoxia-induced hypoxia induced by factor-1α (HIF-1α) and leads to invasion of hypoxic tumors. HIF-1α reduces the expression of c-Met, which can be triggered by vascular puncture caused by VEGF inhibitors, and is selective for migration, invasive tumor cells, and propensity for metastasis through metastasis.

In summary, the novel quinoline compounds of the present invention require a synthetic process suitable for industrial production, high purity products, and multi-targeted tyrosine protein kinase inhibitors, whose main function is to inhibit Tyrosine protein kinase activity plays its role. Of course, the possibility of such compounds inhibiting other disease-associated protein kinases is not excluded.

Summary of the invention

It is an object of the present invention to provide a synthetic process suitable for industrial production which provides a high purity product with a multi-targeted tyrosine protein kinase inhibitor.

In a first aspect of the invention, there is provided a process (2) for the preparation of a compound of formula I:

(2) reacting a compound of formula II with sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, lithium hydroxide, potassium carbonate, sodium hydrogencarbonate, or a combination thereof, and other bases known to those skilled in the art to provide a compound of formula I .

Wherein R _{1 is} selected from the group consisting of hydrogen, OH, NH ₂ ; R _{2 is} selected from the group consisting of ROH, RNH, wherein R is a C ₁ -C ₄ alkyl group, a halogenated C ₁ -C ₄ alkyl group; and Ar is an aryl or heteroaryl group. And may be substituted by halogen, C ₁ -C ₄ alkyl, halogenated C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or halogenated C ₁ -C ₄ alkoxy; Y is 0, 1, 2; X is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, benzoic acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like, and other acids known to those skilled in the art; Z is 0, _1, 2H ₂ O.

In another preferred embodiment, in the step (2), the reaction temperature is from 0 ° C to 50 ° C, and the reaction time is from 1 to 12 hours.

In another preferred embodiment, in the step (2), the reaction is carried out in an inert solvent selected from the group consisting of benzene, dichloromethane, chloroform, tetrahydrofuran, N, N-di Methylformamide, N,N-dimethylacetamide, acetonitrile, ethyl acetate, absolute ethanol, or a combination thereof.

In another preferred embodiment, in the step (2), the molar ratio of the compound of the formula I to the various acids is from 1/0.1 to 1/20.

In another preferred embodiment, the method optionally further comprises the step (1):

Reaction of compound of formula III with compound A provides the compound of formula II:

Wherein R ₂ and Ar are as described above.

In another preferred embodiment, in the step (1), the reaction temperature is from 0 ° C to 50 ° C, and the reaction time is from 1 to 12 hours.

In another preferred embodiment, in the step (1), the reaction is carried out in an inert solvent selected from the group consisting of benzene, dichloromethane, chloroform, tetrahydrofuran, N, N-di Methylformamide, N,N-dimethylacetamide, acetonitrile, ethyl acetate, absolute ethanol, or a combination thereof.

In another preferred embodiment, in the step (1), the reaction can be carried out in the presence or absence of a base; the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogencarbonate, or a combination thereof.

In another preferred embodiment, in the step (1), the molar ratio of the compound of the formula II to the compound A is from 1/0.1 to 1/100.

Advantageous effects of the present invention

Detailed ways

Through the study of the comparative synthetic route, it was finally determined that a compound was prepared from the compound of the formula III as a starting material, and a method for synthesizing the quinoline compound was obtained. The synthetic method is suitable for industrial production, high purity of the product, and has antitumor activity. The compound obtained by the method was identified by hydrogen spectrum and mass spectrometry.

The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention.

Example 1:

Synthesis steps:

Step (1) reaction:

Add 500g of cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinoline-4-oxo to the reactor 2000]-phenyl}-amide benzamide dihydrochloride and N,N-dimethylformamide 2000ml, the temperature of the reaction system was lowered to 0 ° C after stirring and dissolved, and then 1500 g of potassium carbonate was added, and the reaction was carried out for 2 hours at room temperature. The temperature of the reaction system was lowered to 0 ° C, 1250 g of ethyl chloroacetate was added, and the reaction was carried out for 2 hours at room temperature; the temperature of the reaction system was lowered to 0 ° C, 8000 ml of ice water was slowly added, and a large amount of solid was precipitated and stirred for 1 hour. , to all precipitated, suction filtration, washed 3 times with water; the filter cake is further beaten twice with 2 times the amount of absolute ethanol, filtered, and the filter cake is dried at 40-70 ° C for 4-8 hours; 430 g of intermediate 1 is obtained. Light yellow powder. Yield: 80%.

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 6.69 (1H), δ 7.24 (1H), δ 7.18 (1H), δ8 .0(1-NH), δ3.73(3H), δ8.0(1-NH), δ0.90(2H), δ0.90(2H), δ7.64(1H), δ7.24(1H ), δ7.00(1H), δ7.24(1H), δ7.64(1H), δ3.90(2H), δ2.00(1H), δ1.46(2H), δ2.24(2H) , δ2.24(2H), δ1.46(2H), δ3.32(2H), δ4.12(2H), δ1.30(3H)

Step (2) reaction:

Add 420g of intermediate 1 to the reaction kettle, add 8 times the amount of ethanol, reduce the temperature of the system to 0 ° C, and double the amount Add lithium hydroxide to the reaction system, react at room temperature for 4-5 hours; reduce the reaction system to 0 ° C, adjust the pH to 7 with hydrochloric acid; spin at room temperature, add a small amount of tetrahydrofuran and continue to steam; stop the steaming slowly Dichloromethane was added, and a large amount of solid was precipitated by stirring, suction filtration, and the filter cake was washed three times with water, and the filter cake was dried at 40-70 ° C for 4 to 8 hours; 300 g of a compound was obtained. Yield 70%, melting point m.p.214.0-216.2 °C

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 3.73 (3H), δ 3.90 (2H), δ 2.00 (1H), δ1 .46(2H), δ2.24(2H), δ2.24(2H), δ1.46(2H), δ3.52(2H), δ2.09(3H), δ6.69(1H), δ7. 24(1H), δ7.18(1H), δ8.0(1-NH), δ8.0(1-NH), δ7.64(1H), δ7.24(1H), δ0.90(2H) , δ0.90 (2H)

m/z: 640.27

Example 2:

The synthesis method is referred to in Example 1.

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 3.73 (3H), δ 3.9 (2H), δ 2.00 (1H), Δ1.46(2H), δ2.24(2H), δ2.24(2H), δ1.46(2H), δ3.30(2H), δ11.0(1-OH), δ6.69(1H) , δ7.24(1H), δ7.18(1H), δ8.0(1-NH), δ8.0(1-NH), δ7.52(1H), δ7.04(1H), δ7.04 (1H), δ7.52(1H), δ0.90(2H), δ0.90(2H), δ2.35(3H)

m/z: 656.26

Example 3:

The synthesis method is referred to in Example 1.

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 3.73 (3H), δ 3.90 (2H), δ 2.00 (1H), δ1 .46(2H), δ2.24(2H), δ2.24(2H), δ1.46(2H), δ3.25(2H), δ6.0(2-NH), δ6.69(1H), δ 7.24 (1H), δ 7.18 (1H), δ 8.0 (1-NH), δ 8.0 (1-NH), δ 7.64 (1H), δ 7.24 (1H), δ 7.00 ( 1H), δ7.04(1H), δ7.24(1H), δ7.64(1H), δ0.90(2H), δ0.90(2H)

m/z: 641.26

Example 4:

The synthesis method is referred to in Example 1.

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 3.73 (3H), δ 3.90 (2H), δ 2.00 (1H), δ1 .46(2H), δ2.24(2H), δ2.24(2H), δ1.46(2H), δ3.25(2H), δ6.0(2-NH), δ6.69(1H), δ 7.24(1H), δ7.18(1H), δ8.0(1-NH), δ8.0(1-NH), δ7.52(1H), δ7.04(1H), δ7.04( 1H), δ7.52 (1H), δ0.90 (2H), δ0.90 (2H), δ2.35 (3H)

m/z: 655.28

Example 5:

The synthesis method is referred to in Example 1.

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 3.73 (3H), δ 3.90 (2H), δ 2.00 (1H), δ1 .46(2H), δ2.24(2 H), δ2.24(2H), δ1.46(2H), δ3.25(2H), δ6.0(2-NH), δ6.69(1H), δ7.24(1H), δ7.18 (1H), δ8.0(1-NH), δ8.0(1-NH), δ7.62(1H), δ6.95(1H), δ6.95(1H), δ7.62(1H), Δ0.90(2H), δ0.90(2H)

m/z: 659.26

Example 6

The synthesis method is referred to in Example 1.

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 3.73 (3H), δ 3.90 (2H), δ 2.00 (1H), δ1 .46(2H), δ2.24(2H), δ2.24(2H), δ1.46(2H), δ3.25(2H), δ6.0(2-NH), δ6.69(1H), δ 7.24 (1H), δ 7.18 (1H), δ 8.0 (1-NH), δ 8.0 (1-NH), δ 7.53 (1H), δ 6.75 (1H), δ 7.53 ( 1H), δ0.90 (2H), δ0.90 (2H), δ3.73 (3H)

m/z: 671.28

Example 7

The synthesis method is referred to in Example 1.

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 3.73 (3H), δ 3.90 (2H), δ 2.00 (1H), δ1 .46(2H), δ2.24(2H), δ2.24(2H), δ1.46(2H), δ3.30(2H), δ11.0(1-OH), δ6.69(1H), δ 7.24 (1H), δ 7.18 (1H), δ 8.0 (1-NH), δ 8.0 (1-NH), δ 7.62 (1H), δ 6.95 (1H), δ 6.95 ( 1H), δ7.62 (1H), δ0.90 (2H), δ0.90 (2H)

m/z: 660.24

Example 8

The synthesis method is referred to in Example 1.

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 3.73 (3H), δ 3.90 (2H), δ 2.00 (1H), δ1 .46(2H), δ2.24(2H), δ2.24(2H), δ1.46(2H), δ3.52(2H), δ2.09(2H), δ6.69(1H), δ7. 24(1H), δ7.18(1H), δ8.0(1-NH), δ8.0(1-NH), δ7.53(1H), δ6.75(1H), δ6.75(1H) , δ7.53(1H), δ0.90(2H), δ0.90(2H), δ3.73(3H)

m/z: 670.28

Example 9

The synthesis method is referred to in Example 1.

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 3.73 (3H), δ 3.90 (2H), δ 2.00 (1H), δ1 .46(2H), δ2.24(2H), δ2.24(2H), δ1.46(2H), δ3.30(2H), δ11.0(1-OH), δ6.69(1H), δ 7.24 (1H), δ 7.18 (1H), δ 8.0 (1-NH), δ 8.0 (1-NH), δ 7.59 (1H), δ 7.10 (1H), δ 7.10 ( 1H), δ7.59(1H), δ0.90(2H), δ0.90(2H), δ2.59(2H), δ1.24(3H)

m/z: 670.28

Example 10:

The synthesis method is referred to in Example 1.

1H-NMR (400MHZ, CDCl3, TMS, ppm):

δ 7.29 (1H), δ 7.32 (1H), δ 8.55 (1H), δ 6.47 (1H), δ 3.73 (3H), δ 3.90 (2H), δ 2.00 (1H), δ1 .46(2H), δ2.24(2H), δ2.24(2H), δ1.46(2H), δ3.25(2H), δ6.0(2-NH), δ6.69(1H), δ 7.24 (1H), δ 7.18 (1H), δ 8.0 (1-NH), δ 8.0 (1-NH), δ 7.59 (1H), δ 7.10 (1H), δ 7.10 ( 1H), δ7.59(1H), δ0.90(2H), δ0.90(2H), δ2.59(2H), δ1.24(3H)

m/z: 669.30

Example 11: Inhibition of tyrosine kinase activity in vitro screening assay

Study of inhibition of tyrosine kinase activity of the compounds, expressed as IC _50.

experimental method:

The enzyme reaction substrate Poly(Glu, Tyr) _4:1 was diluted to 20 μg/ml with potassium-free PBS, coated with an enzyme plate at 37 ° C for 12-16 hours, and the liquid in the well was discarded; T-PBS was washed. Three times, each time for 10 minutes; the enzyme plate was dried in an oven at 37 ° C; the test sample was added to the wells of the coated enzyme plate (the test sample was first prepared with DMSO to make a stock solution of 10-2 M, and dispensed. Store at -20 ° C, dilute to the desired concentration with the reaction buffer before use, add to the experimental wells to reach the corresponding final concentration in 100 μl reaction system; add ATP and test tyrosine kinase (ATP solution diluted with reaction buffer was added, and test tyrosine kinase diluted with reaction buffer was added); the total volume of the reaction system was 100 ul. Negative control wells and enzyme-free control wells were also established at the same time. The reaction system was placed in a wet box, shaken at 37 ° C for 1 hour in the dark, and T-PBS was washed three times after the reaction; the antibody was added, shaken at 37 ° C for 30 minutes, and washed three times with T-PBS; horseradish was added. Peroxidase-labeled goat anti-mouse IgG, shaken at 37 ° C for 30 minutes, washed three times with T-PBS; add OPD color solution, avoid reaction at room temperature for 1-10 minutes; add 2M H ₂ SO ₄ 50 μl to stop The reaction was measured for AB ₄₉₀ using a tunable wavelength microplate reader.

Table 1 Inhibition of tyrosine kinase activity IC ₅₀ (nM)

Note: 1. (A) 30nM or less;

2. (B) > 30nM to 100nM;

3.(C)>100nM

Example 12: Cell proliferation assay

The proliferation inhibitory activity of the compound on the cells was investigated and expressed by IC ₅₀ .

Experimental method: The cells in the logarithmic growth phase were removed from the culture medium in the culture flask, and the cells were washed once with PBS, collected by centrifugation, centrifuged, resuspended in a medium containing 10% fetal bovine serum, and counted and adjusted to an appropriate concentration. The cell suspension was added to a 96-well plate at 100 ul per well, and the compound was formulated into a 20 mM solution in DMSO. The compound solution and paclitaxel (reservoir 0.2 mM) were diluted with DMSO (10 concentrations), and 5 ul of the gradient-diluted compound were respectively taken. The solution and the paclitaxel solution were added to 495 ul of a medium containing 10% FBS to prepare a test compound solution. 100 ul of the test compound solution was added to the corresponding well of a 96-well plate, and cultured in a carbon dioxide cell incubator for 72 hours. The medium was removed, 150 ul per well of XTT working solution was added, and the carbon dioxide incubator was placed for 2 hours, the microplate was shaken for 5 min, and the absorbance was read by a microplate reader at 450 nm.

Table 2 Cell proliferation inhibition activity IC ₅₀ (μM)

Note: 1. (A) ≤ 10μM;

2. (B) > 10 μM;

The above description is only a preferred embodiment of the present invention, and those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. These improvements and retouchings should also be considered as The scope of the present invention can be variously changed or modified by those skilled in the art, and such equivalent forms are also within the scope defined by the appended claims.

Claims (3)

A method of preparing a compound of formula (I) is provided:

Reaction with a compound of formula II to give a compound of formula I; Wherein R _{1 is} selected from the group consisting of hydrogen, OH, NH ₂ ; R _{2 is} selected from the group consisting of ROH, RNH, wherein R is a C ₁ -C ₄ alkyl group, a halogenated C ₁ -C ₄ alkyl group; and Ar is an aryl or heteroaryl group. And may be substituted by halogen, C ₁ -C ₄ alkyl, halogenated C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or halogenated C ₁ -C ₄ alkoxy; Y is 0, 1, 2; X is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, benzoic acid, tartaric acid, oxalic acid, p-toluenesulfonic acid, and the like, and other acids known to those skilled in the art; Z is 0, 1, 2H ₂ O; the reaction temperature is 0 ° C ~ 50 ° C, the reaction time is 1 ~ 12 hours; The reaction is carried out in an inert solvent selected from the group consisting of benzene, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile. , ethyl acetate, absolute ethanol, or a combination thereof; The reaction can be carried out in the presence or absence of a base; the base is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, lithium hydroxide, potassium carbonate, sodium hydrogencarbonate, or a combination thereof; The molar ratio of the compound of the formula I to the acid is from 1/0.1 to 1/20. The method of claim 1 wherein said method further comprises the step of:

Reaction of compound of formula III with compound A provides the compound of formula II: Wherein R _{2 is} selected from the group consisting of ROH and RNH, wherein R is a C ₁ -C ₄ alkyl group, a halogenated C ₁ -C ₄ alkyl group; Ar is as defined in claim 1; The reaction temperature is 0 ° C ~ 50 ° C, the reaction time is 1 ~ 12 hours; The reaction is carried out in an inert solvent selected from the group consisting of benzene, dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile. , ethyl acetate, absolute ethanol, or a combination thereof; The reaction can be carried out in the presence or absence of a base; the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogencarbonate, or a combination thereof; The molar ratio of the compound of the formula II to the compound A is from 1/0.1 to 1/100. The quinoline compound or the composition thereof obtained by the method of claim 1 is a tyrosine protein kinase inhibitor having multiple targets and has good antitumor activity.